Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders

ABSTRACT

Compounds of general formula (I), where m is 0-8, q is 0-8, a is between 0-4, A signifies a single or double bond, R 1  and R 2  signify hydrogen or lower alkyl, whereby R 1  and R 2  are the same or different and, when m signifies 2-8, R 1  and R 2  in the group CR 1 ═CR 2  can have various significances, R 3  signifies hydrogen or lower alkyl, X signifies hydrogen or —(CH 2 ) b —COR 4  with b=0-4, Y signifies hydrogen, —COR 4 , phenyl or indolyl residue, R 4  signifies hydroxyl, lower alkoxy or the NR 1 R 2  residue, whereby R 1  and R 2  are the same or different, W is optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, as well as physiologically compatible salts, esters, optically active forms, racemates, tautomers, derivatives which can be metabolized in vivo to compounds of general formula (I), and produces medicaments for prophylaxis or therapy of metabolic bone disorders with the compounds.

[0001] The present invention is concerned with rhodanine carboxylic acidderivatives for the treatment and prevention of metabolic bonedisorders, a process for their manufacture as well as medicaments whichcontain these compounds.

[0002] In healthy persons the synthesis and degradation processes inbones is almost in equilibrium, i.e. the activity of the osteoblasts andosteoclasts is balanced. However, if this equilibrium is disturbed infavour of the osteoclasts ancuor to the detriment of the osteoblasts,this leads to a reduction in the bone mass and to a negative change inthe bone structure and function.

[0003] Hitherto, bone resorption inhibitors such as oestrogens,calcitonin and biphosphonates have primarily been used for the treatmentof metabolic bone disorders. The use of these substances is, however,limited and also does not show the desired effect in all cases.Compounds which have a stimulating activity on bone synthesis and inaddition contribute to an increase in an already reduced bone mass areaccordingly of especial significance for the treatment of metabolic bonedisorders.

[0004] Compounds having the rhodanine carboxylic acid structural elementare known as antidiabetics, cytostatics inflammation inhibitors and forthe treatment of cardiovascular illnesses and bacterial infections

[0005] The parathyroid hormone (PTH), a hormone from the parathyroidgland, is the natural ligand of the receptor and an important regulatorfor the maintenance of the calcium level in the body. PTH can stimulatebone formation or bone resorption. In this, it acts as a regulatoryhormone on a series of enzymes, inter alia, on adenylate cydase (cAMPsynthesis) and on ornithine decarboxylase. PTH mobilizes calcium frombones in the case of calcium deficiency, reduces calcium excretion fromthe kidneys and simultaneously improves the resorption of calcium fromthe intestine by an increased synthesis of 1,25-(OH)₂D₃. A normalizationof the calcium level is achieved by the action on these target organs.On the other hand, the incorporation of calcium in bones is stimulatedin the case of an elevated calcium level. This osreoanabolic activity ofPTH and its fragments has been attributed to the activation of adenylatecyclase and of cAMP-dependent protein kinases (Rixon, R. Whitfield, J.et al JMBR 9 (8) 1179-89 (1994).

[0006] Surprisingly, it has now been found that rhodanine carboxylicacid derivatives of the present invention stimulate the PTHreceptor-mediated cAMP formation. Compounds of the present invention areaccordingly suitable for the broad treatment of metabolic bonedisorders. They can be used primarily to good effect where the bonesynthesis is disturbed, i.e. they are especially suitable for thetreatment of osteopenic disorders of the skeletal system such as e.g.osteoporosis, inter alia, osteogenesis imperfecta as well as for thelocal assistance in bone regeneration and osteoinduction such as e.g. inorthopedic and maxillary medical indications, in fracture healing,osteosyntheses, pseudoarthroses and for the healing in of bone implants.However, having regard to these properties they also find use in theprophylaxis of osteoporosis.

[0007] By their influence on bone metabolism medicaments with therhodanine carboxylic acid derivatives of the present invention as activesubstances furthermore form a basis for the local and systemic treatmentof rheumatoid arthritis, osteoarthritis and degenerative arthrosis.

[0008] The object of the present invention are compounds of generalformula (I),

[0009] in which

[0010] m signifies a number between 0-8,

[0011] q signifies a number between 0-8

[0012] a signifies a number between 0-4

[0013] A signifies a single or double bond

[0014] R₁, R₂ signify hydrogen or lower alkyl, whereby R₁ and R₂ can bethe same or different and, when m signifies 2-8, R₁ and R₂ in the groupCR₁═CR₂ can have various significances within the following sequence

[0015] R₃ signifies hydrogen or lower alkyl

[0016] X signifies hydrogen or —(CH₂)_(b)—COR₄ with b=0-4

[0017] Y signifies hydrogen, —COR₄, phenyl or indolyl residue

[0018] R₄ signifies hydroxyl, lower alkoxy or the NR₁R₂ residue, wherebyR₁ and R₂ can be the same or different

[0019] W signifies an optionally mono- or polysubstituted saturated orunsaturated mono-, bi- or tricyde which can contain one or more heteroatoms,

[0020] As a rule, lower alkyl signifies linear or branched alkylresidues with one to six carbon atoms, preferably methyl, ethyl, propyl,i-propyl, butyl, t-butyl, pentyl, hexyl, particularly methyl.

[0021] Alkoxy groups signify a combination of a C₁-C₁₀-alkyl group inaccordance with the above definition with an oxygen atom, e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.

[0022] Under monocycle there are to be understood optionally mono- orpolysubstituted, saturated or unsaturated ring systems with 3-8,preferably 5-7 carbon atoms, which optionally can be interrupted by oneor more hetero atoms, such as nitrogen, oxygen or sulphur, especiallythe phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, morpholinyl, thiamorpholinyl,piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, furyl,thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl or 1,2,4-triazolyl residue, as well as residues such ase.g. phenyl phenyl ether, diphenylmetcne and biphenyl. Substituents arepreferably lower alkyl alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl,acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy,benzyloxybenzyloxy, carboxyl, chiorophenylsulphanyt, dioxymethylene,mercaptoalkyl, nitro, phenoxy, styryl and halogen.

[0023] In the case of the bicycle set forth under W, this is preferablya residue such as the naphthyl, tetrahydronaphthyl, decalinyl,quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl,benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinylresidue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl,tetrahydroquinolinyl benzothiophenyl and benzofuranyl residue, whichoptionally can be mono- or polysubstituted. Substituents are preferablylower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino,alkoxydiakylamino, amino, dialkylamino, benzyl, benzyloxy,benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene,mercaptoalkyl, nitro, phenoxy, styryl and halogen.

[0024] In the case of the tricycle set forth under W, this is preferablya residue such as the anthracene, fluorene, dibenzofuran or carbazole.

[0025] Compounds of formula I wherein W is phenyl or indolyl, m and gare both 0, R₃ is hydrogen and A is a double bond are disclosed e.g. inEP-A-0677 and EP-A-0587377, however for the treatment of Alzheimer'sdisease or as hypoglycemic agents.

[0026] Therefore subject of the present invention are also new compoundsof formula I

[0027] in which

[0028] m signifies a number between 0-8,

[0029] q signifies a number between 0-8

[0030] a signifies a number between 0-4

[0031] A signifies a single or double bond

[0032] R₁, R₂ signify hydrogen or lower alkyl, whereby R₁ and R₂ can bethe same or different and, when m signifies 2-8, R₁ and R₂ in the groupCR₁═CR₂ can have various significances within the following sequence

[0033] R₃ signifies hydrogen or lower alkyl

[0034] X signifies hydrogen or —(CH₂)_(b)—COR₄ with b=0-4

[0035] Y signifies hydrogen, —COR₄, phenyl or indolyl residue

[0036] R₄ signifies hydroxyl, lower alkoxy or the NR₁R₂ residue, wherebyR₁ and R₂ can be the same or different

[0037] W signifies an optionally mono- or polysubstituted saturated orunsaturated mono-, bi- or tricycle which can contain one or more heteroatoms,

[0038] whereas W is not phenyl or indolyl, if m and g are both 0, R₃ ishydrogen and A is a double bond, as well as their physiologicallycompatible salts, esters, optically active forms, racemates, tautomers,as well as derivatives which can be metabolized in vivo to compounds ofgeneral formula (I), as well as the use of these compounds for theproduction of medicaments.

[0039] Preferred are compounds of general formula I in which m signifiesa number between 0 and 4, q signifies the number 0 or 1, a signifies anumber of 0 to 4, A signifies a double bond, R_(1,2) signify hydrogen ormethyl, X signifies hydrogen or —(CH₂)_(b)—COR₄ with b=0-2 and R₄ equalshydroxyl, methoxy or NR₁R₂, Y signifies hydrogen or COR₄, the phenyl orindolyl residue, R₃ signifies hydrogen or methyl and W signifies anoptionally mono- or polysubstituted benzothiophene, phenyl, benzofuran,thiophene, naphthalene, piperidine, cyclohexenyl or biphenyl residue.

[0040] The manufacture of the compounds of general formula (I) ispossible according to methods known per se. Examples of the methods ofsynthesis are set forth in Schemes 1 and 2; whereby R signifies thegroup:

[0041] The rhodanine carboxylic acids and aldehydes used as startingmaterials are either commercially available, known or can be preparedanalogously to the generally known processes.

[0042] Compounds of formula (I) can be administered (sic) in liquid,solid or aerosol form orally, enterally, parenterally, topically,nasally, pulmonary or rectally in all usual non-toxic pharmaceuticallyacceptable carrier materials, adjuvants and additives. The compounds offormula (I) can also be applied locally to/in the bones (optionally withsurgical intervention). The term parenteral embraces subcutaneous,intravenous and intramuscular delivery or infusions. Oral administrationforms can be e.g. tablets, capsules, dragees, syrups, solutions,suspensions, emulsions, elixirs etc., which can contain one or moreadditives from the following groups, such as flavourings, sweeteners,colouring agents and preservatives. Oral administration forms containthe active ingredient together with non-toxic, pharmaceuticallyacceptable carrier materials which are suitable for the production oftablets, capsules, dragees etc., such as e.g. calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; starch,mannitol, methylcellulose, talc, highly dispersible silicic acids, highmolecular fatty acids (such as stearic acid), groundnut oil, olive oil,parafen, miglyol, gelatine, agar-agar, magnesium stearate, beeswax,cetyl alcohol, lecithin, glycerol, animal and vegetable fats, solid highmolecular polymers (such as polyethylene glycol). Tablets, capsules,dragees etc. can be provided with an appropriate coating, e.g. glycerylmono-stearate or glyceryl distearate, in order to prevent undesired sideeffects in the gastrointestinal tract or to give a longer duration ofaction by the delayed absorption in the gastrointestinal tract As theinjection medium there are preferably used sterile injectable aqueous oroily solutions or suspensions which contain the usual additives such asstabilizers and solubilizers. Such additives can be e.g. water, isotonicsaline, 1,3-butanediol, fatty acids (such as oleic acid), mono- anddiglycerides or miglyol. For rectal use there can be used all suitablenon-irritating additives which are solid at normal temperatures andliquid at rectal temperatures, such as e.g. cocoa butter andpolyethylene glycol. Pharmaceutically usual carrier media are used forapplication as aerosols. Creams, tinctures, gels, solutions orsuspensions etc. with the pharmaceutically usual additives are used forexternal application. The dosage can depend n a variety of factors suchas mode of administration, species, age and/or individual condition. Thedoses to be administered daily or at intervals lie at 1-1000mg/individual, preferably at 10-250 mg/individual, and can be taken atone time or divided over several times.

[0043] The compounds of formula (I) can also be applied locally to/inthe bones (optionally with surgical intervention). The applicationdirectly to/in the bones (optionally with surgical intervention) can beeffected locally or carrier-bonded either in solution or suspension,conveniently by infusion or injection. Carrier-bonded compounds offormula (I) can be administered, for example, as gels, pastes, solids oras a coating on implants.

[0044] Biocompatible and preferably biodegradable materials are used asthe carrier. Preferably, the materials themselves also induce woundhealing or osteogenesis.

[0045] For local application it is preferred that the compounds offormula (I) are imbedded in polymer gels or films in order to immobilizethem and to apply these preparations directly on the site of the bone tobe treated. Such polymer-based gels or films consist, for example, ofglycerine, methylcellulose, hyaluronic acid, polyethylene oxides and/orpoloxamers. Also suitable are collagen, gelatines and alginates and aredescribed, for example, in WO 93/00050 and WO 93/20859. Further polymersare polylactic acid (PLA) and copolymers of lactic acid and glycolicacid (PLPG) (Hollinger el al., J. Biomed. Mater. Res. 17 71-82 (.1983))as well as the bone derivative “Demineralized Bone matrix” (DBM)(Guterman et al. Kollagen Rel. Res. 8 419-4319 (1988). Also suitable arepolymers as are used, for example, for the adsorption of TGFβ and whichare described in EP-A 0 616 814 and EP-A-0 567 391 and synthetic bonematrices in accordance with WO 91/18558.

[0046] Likewise suitable as carriers for the compounds of formula (I)are materials which are usually used for the implantation of bonesubstitutes or otherwise of therapeutically active substances. Suchcarriers are based, for example, on calcium sulphate, tricalciumphosphate, hydroxylapatite (sic) and its biodegradable derivatives andpolyanhydrides. Apart from these biodegradable carriers there are alsosuitable carriers which are not biodegradable, but which arebiocompatible. Such carriers are, for example, sintered hydroxylapatite,bioglass, aluminates or other ceramic materials (e.g. calcium aluminiumphosphate). These materials are preferably used in combination with thebiodegradable materials, such as especially polylactic acid,hydroxylapatite, collagen or tricalcium phosphate. Furthernon-degradable carriers are described, for example, in U.S. Pat. No.4,164,560.

[0047] It is especially preferred to use a carrier which liberates thecompounds of formula (I) continuously at the target site. Especiallysuitable for this are e.g. “slow release pellets” from InnovativeResearch of America, Toledo, Ohio, USA. Pellets which release thecompounds of formula (I) over several days, preferably up to 100 dayswith a daily dosage of 1-10 mg/kg per day, are especially preferred.

[0048] Preferred in the scope of the present invention are, apart formthe compounds named in the Examples and compounds derivable by acombination of all of the significances of the substituents set forth inthe claims, the following derivatives as well as their physiologicallycompatible salts, esters, optically active forms, racemates, tautomersas well as derivatives which can be metabolized in vivo to compounds ofgeneral formula (I), as well as the use of these compounds for theproduction of medicaments, Preferred Compounds (PC):

[0049] 1.[5-(9H-Fluoren-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0050] 2.(4-Oxo-5-phenanthren-9-ylmethyl-2-thioxo-thiazolidin-3-yl)-acetic acid

[0051] 3.[5-(3-Anthracen-9-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0052] 4.3-[5-(10-Methyl-anthracen-9-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0053] 5.3-[5-(5-Furan-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0054] 6. 2-(5-Benzylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinicacid

[0055] 7.2-[5-(2-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0056] 8.[4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-benzyl)-thiazolidin-3-yl]-aceticacid

[0057] 9.{5-[3-(2,4-Dimethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0058] 10.3-[4-Oxo-2-thioxo-5-(2,4,5-trimethoxy-benzylidene)-thiazolidin-3-yl]-propionicacid

[0059] 11.3-{4-Oxo-2-thioxo-5-[3-(2,4,6-trimethoxy-phenyl)-allylidene]-thiazolidin-3-yl}-propionicacid

[0060] 12.2-[5-(2,5-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0061] 13.2-[5-(2-Ethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0062] 14.[5-(2-Hydroxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0063] 15.{5-[3-(3-Ethoxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0064] 16.3-[5-(2,3-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0065] 17.3-{4-Oxo-2-thioxo-5-[3-(2,3,4-trihydroxy-phenyl)-allylidene]-thiazolidin-3-yl}propionicacid

[0066] 18.2-[5-(4-Diethylamino-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0067] 19.2-[5-(2-Hydroxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0068] 20.[5-(2-Hydroxy-5-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0069] 21.{5-[3-(2,5-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0070] 22.3-[5-(2-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0071] 23.3-{5-[3-(4-Methoxy-2,3-dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0072] 24.2-[4-Oxo-2-thioxo-5-(2,4,6-trimethyl-benzylidene)-thiazolidin-3-yl]-succinicacid

[0073] 25.2-[5-(2,5-Dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0074] 26.{5-[3-(4-Methoxy-phenoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0075] 27.(5-{3-[3-(4-tert-Butyl-phenoxy)-phenyl]-allylidene}-4-oxo-2-thioxo-thiazolidin-3-yl)-aceticacid

[0076] 28.3-[4-Oxo-2-thioxo-5-(3-#pl-tolyloxy-benzylidene)-thiazolidin-3-yl]-propionicacid

[0077] 29.3-{5-[3-(3-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0078] 30.2-[5-(3,4-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0079] 31.2-[4-Oxo-2-thioxo-5-(3,4,5-trimethoxy-benzylidene)-thiazolidin-3-yl]-pentanedicarboxylicacid

[0080] 32.[5-(3,5-Dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0081] 33.{5-[3-(3-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0082] 34.3-[5-(3-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0083] 35.3-{5-[3-(3-Hydroxy-4-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0084] 36.2-[5-(3,4-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0085] 37.2-[5-(3-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0086] 38.[5-(4-Dimethylamino-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0087] 39.{5-[3-(4-Diethylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0088] 40.3-[4-Oxo-5-(4-phenoxy-benzylidene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0089] 41.3-{5-[3-(4-Methoxy-phenyl)-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0090] 42.2-[5-(3-Benzyloxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0091]43.2-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0092] 44. [5-(4-Butoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0093] 45.[5-(3-Naphthalen-1-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0094] 46.3-[5-(2-Methoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0095] 47.3-{5-[3-(2-Hydroxy-naphthalen-1-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0096] 48.2-[5-(4-Methoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0097] 49.2-(5-Naphthalen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentane-dicarboxylicacid

[0098] 50.[5-(9-Ethyl-9H-carbazol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0099] 51.{5-[3-(1H-Indol-3-yl)-allylidene]-4-oxo-2-thioxo-thiazoidin-3-yl}-aceticacid

[0100] 52.3-[5-(5-Methoxy-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0101] 53. 3-[5-(3-Benzo[1,3]dioxol-5-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0102] 54.2-[5-(4-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0103] 55.[5-(4-Hydroxy-3,5-dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0104] 56.{5-[3-(3-Ethoxy-4-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0105] 57.3-[5-(4-Hydroxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0106] 58.3-[5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0107] 59.2-[5-[4-Isopropyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0108] 60. [5-(4-Ethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0109] 61.[5-(4,4-Diphenyl-but-2-enylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0110] 62.3-[4-Oxo-5-[2-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0111] 63.3-5-(4-Methyl-5-phenyl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0112] 64.2-[5-[2-Hexyl-3-phenyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0113] 65.[4-Oxo-5-(5-phenyl-penta-2,4-dienylidene)-2-thioxo-thiazolidin-3-yl]-aceticacid

[0114] 66.3-{5-[3-(2-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0115] 67.3-{5-[5-(4-Dimethylamino-phenyl)-penta-2,4-dienylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0116] 68.[5-(3-Ethoxy-4-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0117] 69.{5-[3-(4-Diethoxymethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0118] 70.3-5-(4-Dimethylamino-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0119] 71.2-[5-(2,4-Dimethoxy-3-methyl-benzylidene-1-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0120] 72[4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl]-acetic acid

[0121] 73.5-[4-(3-Dimethylamino-propoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0122] 74.{5-[3-(2,4-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0123] 75.3-[5-(2-Methyl-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0124] 76.3-{5-[3-(4-Hydroxy-3-methyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0125] 77.2-[5-(2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0126] 78. [4-Oxo-5-(4-propoxy-benzyl)-2-thioxo-thiazolidin-3-yl]-aceticacid

[0127] 79.{4-Oxo-5-(3-(4-pentyloxy-phenyl)-allylidene]-2-thioxo-thiazolidin-3-yl}-aceticacid

[0128] 80.3-[5-[4-Octyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0129] 81.3-{5-[3-(5-Benzytoxy-1H-indol-3-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0130] 82.2-(5-Benzofuran-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentane-dicarboxylicacid

[0131] 83.[4-Oxo-5-(2,3,4,5,6-pentamethyl-benzyl)-2-thioxo-thiazolidin-3-yl]-aceticacid

[0132] 84.{5-[3-(2-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0133] 85.3-[4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-6-methyl-benzylidene)-thiazolidin-3-yl]-propionicacid

[0134] 86.3-{5-[3-(3-Ethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0135] 87.2-[5-(3,4-Dihydroxy-5-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0136] 88.[5-(3,4-Dimethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0137] 89.{5-[3-(4-Ethoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0138] 90.3-[5-(4-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0139] 91.3-{5-[3-(4-Heptydoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0140] 92.2-(5-Benzo[1,3]dioxol-4-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentanedicarboxylicacid

[0141] 93.[4-Oxo-2-thioxo-5-(2,4,5-trimethyl-benzyl)-thiazolidin-3-yl]-acetic acid

[0142] 94.{5-[3-(4-Decyloxy-phenyl)-allylidene]-4-oxo-²-thioxo-thiazolidin-3-yl}-aceticacid

[0143] 95.3-{5-[3-(4-tert-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0144] 96.{5-[3-(4-Amino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0145] 97.3-[5-(2-tert-Butylsulphanyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0146] 98.3-{5-[3-(4-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0147] 99.2-[5-(4-tert-Butoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0148] 100.[4-Oxo-5-(4-propyl-benzyldene)-2-thioxo-thiazolidin-3-yl]-acetic acid

[0149] 101. [5-(4-Hexyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0150] 102.5-[3-(4-Octyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl)-aceticacid

[0151] 103.3-(5-(4-Dodecyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0152] 104.3-{4-Oxo-5-[3-(4pentyl-phenyl)-allylidene]-2-thioxo-thiazolidin-3-yl}-propionicacid

[0153] 105.2-[5-(3-Amino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0154] 106.[3-(7-Methyl-1H-indol-3-ylmethyl)-4-oxo-2-thioxo-lLiazolidin-3-yl]-aceticacid

[0155] 107.3-[4-Oxo-2-thioxo-5-(2-p-tolyl-ethylidene)-thiazolidin-3-yl]-propionicacid

[0156] 108.3-{5-[3-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0157] 109.[5-(4-Hydroxy-2-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0158] 110.{5-[3-(2,2-Dimethyl-chroman-6-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0159] 111.3-[5-(4-Isopropoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0160] 112.2-[5-(4-Methyl-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0161] 113.{5-[3-(2,3-Dihydro-benzofuran-5-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0162] 114.3-(4-Oxo-5-quinolin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-propionicacid

[0163] 113.3-{5-[5-(4-Diethylamino-phenyl)-penta-2,4-dienylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0164] 116.2-[5-(4-Isobutyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0165] 117.[5-(6-Methoxy-naphthalen-2-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0166] 118.{5-[3-(3,5-Dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0167] 119.3-[5-(1-Hydroxy-naphthalen-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0168] 120.[5-(4-Octadecyloxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0169] 121.{5-[3-(4-Diphenylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0170] 122.3-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin-3-yl]-propionicacid

[0171] 123.3-{5-[3-(4-Dimethylamino-2-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0172] 124.{5-[2-(2-Hydroxy-ethoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0173] 125.(5-{3-[4-(2-Hydroxy-ethoxy)-phenyl]-allylidene}-4-oxo-2-thioxo-thiazolidin-3-yl)-aceticacid

[0174] 126.3-[5-(2-Benzyloxy-ethylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0175] 127.3-{5-[3-(4-tert-Butoxycarbonyloxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0176] 128.2-[5-(2,4-Diethoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0177] 129.[5-(2-Benzyloxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0178] 130.{5-[3-(4-Methanesulphonyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0179] 131.3-[5-(2-Hydroxy-5-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0180] 132.(4-Oxo-5-thiophen-2-ylmethyl-2-thioxo-thiazolidin-3-yl)-acetic acid

[0181] 133.[5-(5-Naphthalen-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0182] 134.3-[4-Oxo-5-(3-thiophen-2-yl-allylidene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0183] 135.3-{5-[3-(2-[1,3]Dioxolan-2-yl-6-fluoro-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0184] 136.2-[5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0185] 137. [5-(4-Benzyl-benzyl)-4-oxo-2-thioxo-thiazohidin-3-yl]-aceticacid

[0186] 138.{5-[5,9-Dimethyl-11-(2,6,6-trimethyl-cyclohex-1-enyl)-undeca-2,4,6,8,10-pentaenylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0187] 139.3-[4-Oxo-5-(1H-pyrrol-2-ylmethylene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0188] 140.3-[5-[3-Furan-2-yl-allylidene)-4-oxo-2-thioxo-thiazoldin-3-yl]-propionicacid

[0189] 141.2-{5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-pentanedicarboxylicacid

[0190] 142.(4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-acetic acid

[0191] 143.[5-(1-Methyl-1H-pyrrol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0192] 144.{5-[3-(2-Hydroxy-4,6-dimethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0193] 145.3-[5-[4-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-tioxo-thiazolidin-3-yl]-propiorlicacid

[0194] 146.3-{5-[3-(5-Benzyloxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0195] 147.2-{5-[4-(Benzo[1,3]dioxol-5-ylmethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-pentanedicarboxylicacid

[0196] 148.[5-(4-Benzyloxy-3,5-dihydroxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0197] 149.{5-[3-(2,5-Bis-benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}aceticacid

[0198] 150.3-[5-(4-Benzyloxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0199] 151.3-[5-(3-Cyclohexyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0200] 152.2-{5-[3-Methyl-5-(2,6,6-trimethyl-cydohex-1-enyl)-penta-2,4-dienylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-pentanedicarboxylicacid

[0201] 153.[5-(3,4-Diethoxy-2,5-dimethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid

[0202] 154.{5-[5-(3,4-Diethoxy-2,3-dimethyl-phenyl)-penta-2,4-dienylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0203] 155.[5-(2-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0204] 156.2-{3-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidin-5-yliden]-propenyl}-benzoicacid

[0205] 157.2-[5-(4-Acetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0206] 158. Methyl4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoate

[0207] 159.4-[3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl]-benzoicacid

[0208] 160.3-{4-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidn-5-ylidenmethyl]-phenyl}-acrylicacid

[0209] 161.3-{4-Oxo-5-[3-(4-oxo-4H-chromen-3-yl)-allylidene]-2-thioxo-thiazolidin-3-yl}-propionicacid

[0210] 162.2-[5-(4-Acetoxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0211] 163.3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoic acid

[0212] 164.4-[3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl]-phenylpropionate

[0213] 165.3-[5-(5,7-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid

[0214] 166.3-{5-[3-(2-Ethoxycarbonylmethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0215] 167.2-5-(8-Carboxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0216] 168.[5-(3,4-Diacetoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0217] 169.{5-[3-(2-Amino-4-oxo-4H-chromen-3-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0218] 170.3-[5-(2-Amino-6,7-dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl-propionic acid

[0219] 171. 3-{5-[3-(6-Ethyl-4-oxo-4H-cchromen-3-yl)-allylidenej-4-oxo-2-thioxo-thiazolidin-3-yl}-propionic acid

[0220] 172.2-[5-(6,8-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedicarboxylicacid

[0221] 173. Methyl2-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoate

[0222] 174. Methyl3-[3-[3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl]-1H-indole-6-carboxylate

[0223] 175.3-{5-[3-(4-Acetoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0224] 176.3-[4-Oxo-5-(3-phenyl-but-2-enylidene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0225] 177.2-(4-Oxo-2-thioxo-5-(1-#pl-tolyl-ethylidene)-thiazolidin-3-yl]-pentane-dicarboxylicacid

[0226] 178.{5-(1-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0227] 179.{5-[1-(3,4-Dichloro-phenyl)-ethyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-aceticacid

[0228] 180.[4-Oxo-5-(3-thiophen-2-yl-but-2-enylidene)-2-thioxo-thiazolidin-3-yl]-aceticacid

[0229] 181.3-[4-Oxo-5-(11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-3-ylmethylene)-2-thioxo-thiazolidin-3-yl]-propionicacid

[0230] 182.3-{5-[3-(3,5-Dihydroxy-phenyl)-but-2-enylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionicacid

[0231] 183.2-[5-(4-Hydroxy-3-methobenzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0232] 184.2-[5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0233] 185. 2-(4-Oxo-5-phenthylidene-2-thioxo-thiazolidin-3-yl)-succinicacid

[0234] 186.2-5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0235] 187.2-[4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl]-succinicacid

[0236] 188.2-[5-(4-Allyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0237] 189.2-[4-Oxo-5-(4-pyrrolidin-1-yl-benzylidene)-2-thioxo-thiazolidin-3-yl]-succinicacid

[0238] 190.2-(5-(3,5-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0239] 191.2-{5-[3-(4-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0240] 192.2-[4-Oxo-5-(4-propyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-succinicacid

[0241] 193.2-[5-(2-Ethoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-y]-succinicacid

[0242] 194.2-[5-(3-Furan-2-yl-2-methyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0243] 195.2-{5-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0244] 196.2-{5-[3-(4-tert-Butyl-phenyl)-2-methyl-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0245] 197.2-{5-[3-(2-Hydroxy-ethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0246] 198.2-{5-[3-(4-Hydroxy-3,5-dimethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0247] 199.2-[5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0248] 200.2-[5-(2,4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-tniazolidin-3-yl]-succinicacid

[0249] 201.2-(4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl-succinic acid

[0250] 202.2-[5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0251] 203.2-[5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazoiidin-3-yl]-succinicacid

[0252] 204.2-[5-(3-Carboxy-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0253] 205.2-[5-(4-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0254] 206.2-[5-(6-Methyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0255] 207.2-[5-(6-Isopropyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid

[0256] 208.2-{5-[1-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-succinicacid

[0257] The following Examples show some process variants which can beused for the synthesis of the compounds in accordance with theinvention. However, they are not intended to be a limitation of theobject of the invention. The structure of the compounds was proven by¹H- and, where necessary, by ¹³C-NMR spectroscopy. The purity of thesubstances was determined by C, H, N, P analysis as well as bythin-layer chromatography.

EXAMPLE 1

[0258] General Process A

[0259] 5 mmol of aldehyde of the formula R—CO, wherein R has thesignificance given above, and 5 mmol of4-oxo-2-thioxo-thiazolidin-3-ylcarboxylic acid derivative are heated atreflux for 10 hours together with 15 mmol of sodium acetate and 15 ml ofglacial acetic acid. After cooling, the mixture is poured into H₂O. Theprecipitate is filtered off under suction, rinsed with H₂O and dried.For purification, it is chromatographed over silica gel with ethylacetate/heptane (2:1).

[0260] The preparation of 2-(4-oxo-2-thioxo-thiazolidin-3-yl)-glutaricacid and 2-(4-oxo-2-thioxo-thiazolidin-3-yl)-succinic acid is effectedaccording to Chem. Heterocycl. Compd. EN 3 528-30 (1967).

[0261]2-(5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinicacid (1) Yellow crystals; m.p. 240° C. (dec.)

[0262] 2-(5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentanedioicacid (2) Yellow crystals; m.p. 220-1° C.

[0263]2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3-phenyl-propionicacid (3) Yellow crystals; m.p. 160° C. (dec.)

[0264]2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3-(1H-indol-3-yl)-propionicacid (4) Orange crystals; m.p. 140° C. (dec.)

[0265][5-(5-Acetylamino-benzo[b]thiophen-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (5) Yellow crystals; m.p. >240° C.

[0266]5-[3-(4-Methoxy-2,5-dimethyl-phenyl)-allyliden]-4-oxo-2-thioxo-thiazoiidin-3-yl-aceticacid (6) Red crystals; m.p. >240° C.

[0267]5-[3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (7) Yellow crystals; m.p. >240° C.

[0268][5-(2,3-Dihydro-benzofuran-5-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (8) Yellow crystals; m.p. 246-7° C.

[0269] (4-Oxo-5-thiophen-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-aceticacid (9) Yellow crystals; m.p. 237-9° C.

[0270] (5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid(10) Yellow crystals; m.p. 292-4° C.

[0271][5-(3-Naphthalen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (11) Orange crystals; 275-7° C.

[0272][5-(4-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid(12) Yellow crystals; m.p. 244-6° C.

[0273] [5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (13) Red crystals; m.p. >240° C.

[0274][5-(4-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid(14) Yellow crystals; m.p. 230-2° C.

[0275][5-(4-Methoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (15) Yellow crystals; m.p. 240° C.

[0276] [5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazoldin-3-yl]-acetic acid(16) Orange crystals; m.p. >240° C.

[0277][5-(4-Methoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (17) Yellow crystals; m.p. 235-6° C.

[0278]2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentanedioicacid (18) Yellow crystals; m.p. 130° C. (dec.)

[0279][5-(4-Benzyloxy-35-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (19) M.p. 128-30° C.

[0280][5-(3,4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (20) Yellow crystals; m.p. 187-8° C.

[0281][5-(3-Biphenyl-yl-allylidene)-4-oxo-2-thioxo-Lhiazolidin-3-yl]-aceticacid (21) Orange crystals; m.p. 130° C. (dec.)

[0282]5-[1-Methyl-3-[2,6,6-trimethyl-cyclohex-1-enyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (22) Brown crystals; m.p. 100° C. (dec.)

[0283][5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (23) Yellow crystals; m.p. >240° C.

[0284]2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinicacid (24) Brown crystals; m.p. 240° C. (dec.)

[0285][5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (25) Orange crystals; m.p. 120-1° C.

[0286][5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (26) Yellow crystals; m.p. 205-6° C.

[0287]5-[1-[3,5-Dihydroxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid Yellow crystals; m.p. 184-8° C.

[0288]5-[-(4-Carboxymethoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (28) Yellow crystals; m.p. 111-20° C. (dec.)

[0289](4-Oxo-2-thioxo-5-(2,3,4-trihydroxy-benzylidene)-thiazolidin-3-yl)-aceticacid (29) Ochre-coloured crystals; m.p. 263° C. (dec.)

[0290][5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (30) Pale brown crystals; m.p. 194° C. (dec.)

[0291][5-(3-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (31) Yellow crystals; m.p. 178-81° C.

[0292]3-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid (32) Yellow crystals; m.p. 188-91° C.

[0293]2-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid (33) Yellow crystals; m.p. 125-8° C.

[0294][5-(5-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (34) Orange crystals; m.p. 130-3° C.

[0295]5-[4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (35) Yellow crystals; m.p. 172-3° C.

[0296]5-[4-(Benzo[1,3]dioxol-5-ylmethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (36) Yellow crystals; m.p. 206-7° C.

[0297]5-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin-3-yl]-pentanecarboxylicacid (37) m.p. 212-4° C.

[0298]5-[4-(3-Methoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (38) Yellow crystals; m.p. 191-3° C.

[0299][5-(4-Hydroxy-3,5dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (39) Orange crystals; m.p. 277-9° C.

[0300][5-(4-Benzyloxy-3,3-dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (40) M.p. 178-80° C.

[0301][5-(2,5-Bisbenzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (41) Yellow crystals; m.p. 196-8° C.

[0302][4-Oxo-2-thioxo-5-(3,4,5-triacetoxy-benzylidene)-thiazolidin-3-yl]-aceticacid (42) Orange crystals; m.p. 200° C. (dec.)

[0303]5-(3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxa-2-thioxo-thiazolidin-3-yl-aceticacid (43) Red crystals; m.p. 252-30C.

[0304](5-Cyclohex-3-enybnethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid(44) Beige crystals; m.p. 180-2° C.

[0305] [4-Oxo-5-(3-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl]-aceticacid (45) Orange crystals; m.p. 108-11° C.

[0306]5-(3-Methyl-5-(2,6,6trimethyl-cyclohex-1-enyl)-penta-2,4-dienyliden]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (46) Orange crystals; m.p. 153-5° C.

[0307]5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-3-methyl-2-thioxo-thiazolidin-4-one(47) Yellow crystals; m.p. >240° C.

[0308] Methyl[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetate(48) Yellow crystals; m.p. 165-70° C.

[0309]2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-N,N-diethyl-acetamide(49) Yellow crystals; m.p. 223-5° C.

[0310] Methyl5-[3-(5,6-diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetate(50) Violet crystals; m.p. 211-5° C.

[0311]2-5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-N,N-diethyl-acetamide(51) Red crystals; m.p. 210-2° C.

[0312] Benzyl4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl)-piperidine-1-carboxylate(52) Yellow crystals; m.p. 114-5° C.

[0313]5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-1-enyl)-nona-2,4,6,8-tetraenylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (53) Black (sic) crystals; m.p. 144° C. (dec.)

[0314][5-(3,4-Dihydroxy-2,3-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (54) Yellow crystals; m.p. >240° C.

[0315][5-(3,4-Diethoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (55) Ochre coloured crystals; m.p. 185-90° C.

[0316]5-[3-(3,4-Diethoxy-2,5-dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (56) Green crystals; m.p. 210° C. (dec.)

[0317]5-[5-Methyl-7-[2,6,6-triethyl-cyclohex-1-enyl)-hepta-2,4,6-trienyliden]-4-oxo-2-thioxo-thiazolidin-3-yl-aceticacid (57) Black crystals; m.p. 192-5° C.

[0318]3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-propionicacid (58) Yellow crystals; m.p. 174-6° C.

[0319]3-(4-Oxo-2-thioxo-5-(2,6,6-trimetyl-cyclohex-1-enylmethylene)-thiazolidin-3-yl]-propionicacid (59) Yellow-orange crystals; m.p. 166-8° C.

[0320]3-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid (60) Yellow crystals; m.p. 218-9° C.

[0321]3-(5-Naphthalen-1-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-propionicacid (61) Orange crystals; m.p. 159-61° C.

[0322]3-[5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionicacid (62) Orange crystals; m.p. 246-8° C.

[0323][5-(4-Dibutylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (63) Orange crystals; m.p. 186-8° C.

[0324] [4-Oxo-5-(4-pentyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-aceticacid (64) Yellow crystals; m.p. 160-2° C.

[0325][5-(3-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid(65) Yellow crystals; m.p. 193-6° C.

[0326][4-Oxo-2-thioxo-5-(2,4,5-trirmethyl-benzylidene)-thiazolidin-3-yl]-aceticacid (66) Yellow crystals; m.p. 234-6° C.

[0327][5-(2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid(67) Yellow crystals; m.p. 148-50° C.

[0328] [5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (68) Yellow crystals; m.p. 234-6° C.

[0329][5-(4-Methoxy-2,3-dinethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (69) Yellow crystals; m.p. 215-7° C.

[0330][5-(4-Hydroxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (70) Orange crystals; m.p. 238-40° C.

[0331]5-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl)-2-hydroxy-benzoicacid (71) Yellow crystals; m.p. >260° C.

[0332]3-5-[1-Methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-propionicacid (72) Orange crystals; m.p. 160-1° C.

[0333][5-(1,4-Dihydroxy-10-methoxy-5,8-dimethyl-3,7-dioxo-1,3-dihydro-7H-benzo[e]furo[3′,4′:3,4]benzo[b][1,4]dioxepin-11-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (73) Dark green crystals; m.p. >260° C.

[0334][5-(2-Methyl-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (74) Brown crystals; m.p. 268-70° C.

[0335][5-(3,4-Diacetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceticacid (75) Yellow crystals; m.p. 193-53° C.

EXAMPLE 2

[0336] Compounds of general formula (I) were investigated in a suitableassay for the capability of stimulating cyclic adenylate cyclase. TABLEI % cAMP Example No. Name (Test conc. 50 μM) 32-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo- 82-thioxo-thiazolidin-3-yl]-3-phenyl-propionic acid 13[5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-4- 10oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 16[5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2- 8thioxo-thiazolidin-3-yl]-acetic acid 225-[1-Methyl-3-(2,6,6-trimethyl-cydohex-1-enyl)- 10allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid 23[5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2- 8thioxo-thiazolidin-3-yl]-acetic acid 25[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2- 40thioxo-thiazolidin-3-yl]-acetic acid 465-[3-Methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta- 302,4-dienylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid 593-[4-Oxo-2-thioxo-5-(2,6,6-trimethyl-cyclohex-1- 15enylmethylene)-thiazolidin-3-yl]-propionic acid 603-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo- 202-thioxo-thiazolidin-3-yl]-propionic acid 723-5-[1-Methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)- 15allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-propionic acid

1. Use of compounds of general formula (I)

in which m signifies a number between 0-8, q signifies a number between0-8 a signifies a number between 0-4 A signifies a single or double bondR₁, R₂ signify hydrogen or lower alkyl, whereby R₁ and R₂ can be thesame or different and, when m signifies 2-8, R₁ and R₂ in the groupCR₁═CR₂ can have various significances within the following sequence R₃signifies hydrogen or lower alkyl X signifies hydrogen or—(CH₂)_(b)—COR₄ with b=0-4 Y signifies hydroxyl, —COR₄, phenyl orindolyl residue R₄ signifies hydroxyl, lower alkoxy or the NR₁R₂residue, whereby R₁ and R₂ can be the same or different W signifies anoptionally mono- or polysubstituted saturated or unsaturated mono-, bi-or tricycle which can contain one or more hetero atoms, for thepreparation of medicaments for the treatment and prevention of metabolicbone disorders,
 2. Compounds of general formula (I)

in which m signifies a number between 0-8, q signifies a number between0-8 a signifies a number between 0-4 A signifies a single or double bondR₁, R₂ signify hydrogen or lower alkyl, whereby R₁ and R₂ can be thesame or different and, when m signifies 2-8, R₁ and R₂ in the groupCR₁═CR₂ can have various significances within the following sequence R₃signifies hydrogen or lower alkyl X signifies hydrogen or—(CH₂)_(b)—COR₄ with b=0-4 Y signifies hydroxyl, —COR₄, phenyl orindolyl residue R₄ signifies hydroxyl, lower alkoxy or the NR₁R₂residue, whereby R₁ and R₂ can be the same or different W signifies anoptionally mono- or polysubstituted saturated or unsaturated mono-, bi-or tricycle which can contain one or more hetero atoms, whereas W is notphenyl or indolyl, if m and g are both 0, R₃, is hydrogen and A is adouble bond, as well as their physiologically compatible salts, esters,optically active forms, racemates, tautomers, as well as derivativeswhich can be metabolized in vivo to compounds of general formula (I) 3.Medicament containing at least one compound of general formula (I)according to claim 2 in admixture with usual pharmaceutical adjuventsand carrier material